Lee Suyeon, Ku Sae-Kwang, Bae Jong-Sup
College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, Kyungpook National University, Daegu, 41566, Republic of Korea.
Department of Anatomy and Histology, College of Korean Medicine, Daegu Haany University, Gyeongsan, 38610, Republic of Korea.
Chem Biol Interact. 2016 Aug 25;256:266-73. doi: 10.1016/j.cbi.2016.07.024. Epub 2016 Jul 25.
The screening of bioactive compound libraries can be an effective approach for repositioning FDA-approved drugs or discovering new treatments for human diseases. Previous studies have reported polyphosphate (PolyP)-mediated vascular inflammatory responses such as disruption of vascular integrity. Dabrafenib is a B-Raf inhibitor and initially used for the treatment of metastatic melanoma therapy. This study illustrates drug repositioning with dabrafenib (DAB) for the modulation of PolyP-mediated vascular inflammatory responses in human umbilical vein endothelial cells (HUVECs) and mice. The survival rates, septic biomarker levels, behavior of human neutrophils, and vascular permeability were determined in PolyP-activated HUVECs and mice. Dabrafenib suppressed the PolyP-mediated vascular barrier permeability, upregulation of inflammatory biomarkers, adhesion/migration of leukocytes, and activation and/or production of nuclear factor-κB, tumor necrosis factor-α, and interleukin-6. Furthermore, dabrafenib demonstrated protective effects on PolyP-mediated lethal death and the levels of the related septic biomarkers. Therefore, these results indicated the therapeutic potential of dabrafenib on various systemic inflammatory diseases, such as sepsis or septic shock.
筛选生物活性化合物库可能是重新定位FDA批准药物或发现人类疾病新疗法的有效方法。先前的研究报道了多聚磷酸盐（PolyP）介导的血管炎症反应，如血管完整性破坏。达拉非尼是一种B-Raf抑制剂，最初用于治疗转移性黑色素瘤。本研究阐述了用达拉非尼（DAB）重新定位药物，以调节人脐静脉内皮细胞（HUVECs）和小鼠中PolyP介导的血管炎症反应。在PolyP激活的HUVECs和小鼠中测定了存活率、脓毒症生物标志物水平、人中性粒细胞的行为和血管通透性。达拉非尼抑制了PolyP介导的血管屏障通透性、炎症生物标志物的上调、白细胞的粘附/迁移以及核因子-κB、肿瘤坏死因子-α和白细胞介素-6的激活和/或产生。此外，达拉非尼对PolyP介导的致死性死亡和相关脓毒症生物标志物水平具有保护作用。因此，这些结果表明达拉非尼对各种全身性炎症疾病，如脓毒症或脓毒性休克具有治疗潜力。
